1. Field of the Invention
The present invention relates to osmotic delivery systems for delivering beneficial agents, and more particularly, to an osmotic delivery system flow modulator.
2. Description of the Related Art
Controlled delivery of beneficial agents, such as drugs, in the medical and veterinary fields is accomplished by a variety of methods. One method of controlled prolonged delivery of beneficial agents involves the use of osmotic delivery systems. These devices can be implanted to release beneficial agents in a controlled manner over a pre-selected time or administration period. In general, osmotic delivery systems operate by imbibing fluid from the outside environment and releasing corresponding amounts of the beneficial agent.
Osmotic delivery systems, commonly referred to as “osmotic pumps,” generally include some type of a capsule or enclosure having a wall which selectively permits liquid to enter the interior of the enclosure which contains a liquid attracting osmotic agent. The absorption of liquid by the osmotic agent within the enclosure creates osmotic pressure within the enclosure which, in turn, causes the beneficial agent to be delivered from the enclosure. The osmotic agent may be the beneficial agent and/or a formulation containing the same delivered to the patient. However, in many cases, a separate osmotic agent is used specifically for its ability to draw liquid into the enclosure.
When a separate osmotic agent is used, the osmotic agent may be separated from the beneficial agent within the osmotic delivery system enclosure by a dividing member or movable piston. The structure of the osmotic delivery system does not permit the enclosure to expand when the osmotic agent takes in water and swells. As the osmotic agent expands, it causes the beneficial agent to be discharged through an orifice or delivery port in the enclosure at generally the same rate as a liquid, which is typically water, enters the osmotic agent by osmosis. Osmotic delivery systems may, be designed to deliver a beneficial agent at a controlled constant rate, a varying rate, or in a pulsatile manner.
In some known osmotic delivery systems, the osmotic agent is typically shaped as an osmotic tablet, and is placed inside the enclosure. A semipermeable membrane plug is then typically placed in an opening in the enclosure through which the tablet was inserted. The semipermeable membrane plug acts as the wall which selectively permits liquid to enter the interior of the enclosure. Known semipermeable membrane plugs are typically a cylindrical member with ribs, and operate in the same manner as a cork. These semipermeable membrane plugs seal the interior of the enclosure from the exterior environment of use, only permitting certain liquid molecules from the environment of use to permeate through the semipermeable membrane plug into the interior of the enclosure. The rate that the liquid permeates through the semipermeable membrane plug controls the rate at which the osmotic agent expands and drives a desired concentration of beneficial agent from the delivery system through the delivery port. Osmotic delivery systems may control the rate of delivery of the beneficial agent by varying the permeability coefficient of the semipermeable membrane plug.
In known osmotic delivery systems, the beneficial agent exits the osmotic delivery system enclosure through a delivery port. Such delivery ports are typically fashioned in a plug-like member which is inserted into an opening of the osmotic delivery system enclosure. The opening of the enclosure into which the delivery plug is inserted is typically opposite the end of the enclosure which holds the semipermeable membrane plug. Thus, in assembling these osmotic delivery systems, the dividing member is first inserted into the enclosure. Then the osmotic agent or agents are inserted into the enclosure, and the semipermeable membrane plug is inserted into the opening through which the dividing member and osmotic agents where inserted. Thereafter, if the osmotic delivery system enclosure includes two openings located opposite from each other, the system is rotated 180°, and the beneficial agent is inserted into the enclosure through the opening through which the delivery plug is to be inserted. After the desired amount of beneficial agent has been inserted into the enclosure, the delivery plug having the delivery port is then inserted into the opening through which the beneficial agent was inserted. The delivery plug effectively seals the enclosure from the exterior environment, except for the delivery port.
When the osmotic delivery system with the delivery plug is placed in the environment of use, liquid is imbibed through the semipermeable membrane plug by osmosis, causing the osmotic agent to expand and causing the beneficial agent to flow through the delivery port in the delivery plug. Thus, the beneficial agent exits the enclosure of the osmotic delivery system through the delivery port, and is delivered to the environment of use.
One problem associated with the above-described osmotic delivery system, is that air or gas is frequently trapped above the beneficial agent as the delivery plug is inserted into the osmotic delivery system enclosure. When liquid begins to be imbibed by the osmotic agent through the membrane plug, the osmotic agent expands and drives the dividing member, compressing the beneficial agent to be delivered through the delivery port. Because of air pockets trapped in the compartment or within the beneficial agent formulation itself, the osmotic pressure must compress the air pockets before the incompressible beneficial agent will be delivered through the delivery channel in the delivery plug. This is problematic because the start-up period to delivery of the beneficial agent is delayed by the amount of time during which the air pockets are compressed. The time to “start-up” of delivery generally refers to the time from insertion into the environment of use until the beneficial agent is actually delivered at a rate not less than approximately 70% of the intended steady-state rate. The start-up period may be delayed up to several days or weeks, depending upon the size of the air gaps and the flow rate of the system. Delayed start-up of beneficial agent delivery is a significant problem in osmotic delivery systems. Furthermore, air might be expelled from the osmotic delivery system and cause serious health risks to, for example, humans having implanted osmotic delivery systems, depending on where the system is implanted.
If the osmotic delivery system includes a delivery plug with a very small delivery path or channel, the trapped air may completely prevent the flow of beneficial agent from the delivery channel and/or cause the beneficial agent to be delivered in sporadic bursts.
Another problem associated with the above-described osmotic delivery system is that surplus beneficial agent is typically expelled from the enclosure when the delivery plug is inserted into the enclosure which contains the beneficial agent. Surplus beneficial agent is necessary to ensure that as much air as possible escapes the delivery enclosure. This expelled beneficial agent must be cleaned from the osmotic delivery system enclosure, and makes it difficult to precisely determine the amount of beneficial agent within the osmotic delivery system and the amount of beneficial agent eventually delivered. This wasted agent problem is even more dramatic because most beneficial agents are extremely expensive, and the surplus agent cannot be recovered for re-use. In some instances, as much as forty microliters of beneficial agent may be expelled during the insertion process.
The delivery channel or orifice in the delivery plug which has been inserted in the above-described osmotic delivery systems is the site of interaction between the beneficial agent and the external environment of use. One constraint of certain delivery paths of known delivery plugs is that they must be small enough, either in length and/or interior cross-sectional area, such that the average velocity of active agent out of the delivery system enclosure is higher than the inward flow of liquid into the delivery system from the environment of use. Thus, these delivery channels or orifices in the delivery plug serve the important function of isolating the beneficial agent from liquids and particulate in the external environment of use, since any contamination of the beneficial agent by such external substances may adversely affect the utility of the beneficial agent. For example, the inward flux of materials from the environment of use due to diffusion through the delivery orifice may contaminate the interior of the capsule, destabilizing, diluting, or otherwise altering the beneficial agent formulation. It has been particularly problematic to prevent the diffusion of liquids from the environment of use through the delivery orifice of known osmotic delivery systems such that the utility of the beneficial agent is not impaired, while also obtaining the desired delivery rate of beneficial agent from the osmotic delivery system.
Still another problem associated with the above-described osmotic delivery system is that after the delivery plug has been inserted into the enclosure of the osmotic delivery system, the end of the system with the delivery plug inserted therein must be capped. This capping process is necessary to prevent the beneficial agent from evaporating through the delivery channel or orifice in the delivery plug during the period of time before the osmotic delivery system is inserted into its environment of use. Thus, during the implantation procedure, the cap must be removed prior to implantation of the unit, further complicating the implantation process and the assembly process of the osmotic delivery system.
Because of the above-identified problems associated with current osmotic delivery systems, it is costly and particularly difficult to administer beneficial agents from osmotic delivery systems at controlled delivery rates.